1. Field of the Invention
The present invention is directed to an improved method of making cyclopentyl 2-thienyl ketone, tiletamine and tiletamine acid addition salts, such as tiletamine hydrochloride.
2. Description of the Prior Art
U.S. Pat. No. 3,522,273 ('273) discloses a method of making tiletamine, or 2-amino-2-(2'-thienyl)cyclohexanone, and tiletamine acid addition salts, such as the hydrochloride.
As disclosed in the '273 patent, there are two routes to the synthesis of tiletamine hydrochloride, based on cyclopentyl 2-thienyl ketone (Scheme 1) or tetrahydro-2-pyranyl ether of cyclopentanone cyanohydrin (Scheme 2) as starting compounds, as follows: ##STR1##
Due to availability of the starting compound, lower number of separate steps, lower raw material and operational costs, Scheme 1 is more promising than Scheme 2. However, both Schemes have several shortcomings. First, each step of the synthesis requires a different solvent. Multiple solvents complicate the post-reaction work-up, isolation and solvent recovery steps, and add significantly to the manufacturing cost of the process. In addition, solvents such as carbon tetrachloride and ether are restricted solvents. Moreover, ether is difficult to recover industrially and highly flammable. Second, the processes typically call for multiple isolations and purifications of the intermediates, which substantially effects the operational cost of commercial manufacture.
Cyclopentyl 2-thienyl ketone has been prepared by the Friedel-Crafts reaction of thiophene with initially pre-formed cyclopentanecarboxylic acid chloride (Scheme 3), as disclosed in U.S. Pat. No. 5,597,832 or with tetracyclopentylcarboxysilane (Scheme 4), Jur'ew, Yu K., et al. Zh. Obshch-Khim.; 26, 1956, 3341-3343: ##STR2##
Both Schemes 3 and 4 have the same major shortcoming--stannic chloride is used as a catalyst for the Friedel-Crafts reaction. In addition to its cost, stannic chloride introduces a heavy metal contamination to the process waste stream which is a major problem during manufacture.
It is also known, that cyclopentyl 2-thienyl ketone can be prepared from N'-tosylcyclopentylamidine by reaction with 2-thienyl lithium (Scheme 5), see Clerici, F. et al. Synthesis, 11, 1987, 1025-1027: ##STR3##
This Scheme 5 approach has some scientific interest, but is not desirable from a commercial production standpoint.
In accordance with the present invention, we have discovered alternatives to the original acylation routes to synthesize cyclopentyl 2-thienyl ketone. It has been found that cyclopentanecarboxylic acid chloride can be reacted with thiophene using a solid catalyst, other than stannic chloride, at unexpectedly high yields, to avoid the stannic chloride (heavy metal) waste stream contamination. In accordance with a preferred embodiment of the present invention, aluminum trichloride or graphite are the catalysts of choice for the Friedel-Crafts reaction of cyclopentanecarboxylic acid chloride and thiophene (Scheme 6(b) and (c)):
Scheme 6 (Non-tin-containing Catalytic Friedel-Crafts Reaction)
The synthesis of cyclopentanecarboxylic acid chloride, in accordance with the following reaction (a), can be achieved by reacting cyclopentanecarboxylic acid with thionyl chloride, with or without a solvent. In accordance with a preferred embodiment of the present invention, the same solvent, preferably o-dichlorobenzene, can be used for reaction (a) and the following reactions (b) or (c) so that solvent removal is unnecessary between reactions for isolation of intermediates, e.g., after reaction (a). ##STR4##
As shown in the prior art method of Scheme 3, the prior art reaction requires a tin-containing catalyst, such as stannic chloride, and methylene chloride as a solvent for the reaction of cyclopentanecarboxylic acid chloride with thiophene to form cyclopentyl 2-thienyl ketone. In accordance with an important feature of the present invention, it has been found that other, solid, less waste stream-polluting catalysts can be used for the synthesis of cyclopentyl 2-thienyl ketone by the reaction of cyclopentanecarboxylic acid chloride and thiophene, while achieving new and unexpected yields, as shown in the following reactions (b) and (c): ##STR5##
Aluminum trichloride is both cheaper than stannic chloride and it is easier to deal with as a waste stream. The successful use of graphite as a catalyst for the reaction of cyclopentanecarboxylic acid chloride and thiophene provides a mild and ecologically friendly method for carrying out the Friedel-Crafts reaction. The additional advantage of such an approach includes easier work up, which only requires a simple filtration of the solid catalyst for isolation of the cyclopentyl 2-thienyl ketone reaction product.
The ortho-dichlorobenzene (C.sub.6 H.sub.4 Cl.sub.2) solvent used in the reaction (a) of cyclopentanecarboxylic acid and thionyl chloride (SOCl.sub.2), and in reaction (b) or (c), was also used in the following reaction Schemes 7 and 8. However, other solvents can be used in accordance with the present invention, such as chlorobenzene or dichloroethane as well. Any non-reactive hydrocarbon solvent or chlorinated hydrocarbon solvent is suitable for the reactions of Schemes 6-9 described herein. Higher boiling solvents, having a boiling point of at least about 100.degree. C., are preferred so that the thermal rearrangement reaction of Scheme 9 can be performed at the solvent reflux temperature, at a temperature of at least 100.degree. C., in a commercially acceptable time period. The o-dichlorobenzene is most advantageous since it forms an azeotropic mixture with water for stripping off the water with the o-dichlorobenzene to achieve the most economical drying of intermediates and product. Further, by using the same solvent in sequential steps of the synthesis, it is not necessary to isolate intermediate reaction products from the solvent and unreacted reactants before proceeding with the next sequential step of the process--making the process extremely more commercially viable. The amount of solvent, e.g., o-dichlorobenzene, used in the reactions should be sufficient to dissolve solid reactants. Reaction initiators, such as dimethylformamide, can be added to speed the reaction(s), but are not essential for achieving reactions with excellent yields.
Halogenation (bromination) of the crude cyclopentyl 2-thienyl ketone in o-dichlorobenzene solution at room temperature gave the corresponding .alpha.-halogenated ketone with a high purity, usually 97-99% by GC, area % analysis (Scheme 7). ##STR6##
A work up procedure after the bromination step is a simple evaporation of the solvent, which can be collected and recycled to any step of the process. Evaporation of the o-dichlorobenzene removes residual hydrogen bromide as well. A crude material, without any purification, was carried through directly to the next amination step. A 75% wt/wt solution of .alpha.-bromoketone in o-dichlorobenzene was used to prevent solidification of the starting material during amine addition. The amination reaction resulted in 96% pure (GC, area % analysis) product (Scheme 8). ##STR7##
An excess of ethylamine, used in the reaction, was evaporated from the reaction mixture under mild vacuum, and the ethylamine was recovered and recycled. An ethylamine hydrobromide salt by-product was washed out with water. A solution of crude 1-hydroxycyclopentyl 2'-thienyl N-ethyl ketimine in o-dichlorobenzene was refluxed for 1.5 hours at a temperature of at least about 100.degree. C., preferably about 180.degree. C. to about 230.degree. C., e.g. 220.degree. C. to 225.degree. C., to produce 90% pure (GC, area % analysis) tiletamine free base by the thermal rearrangement reaction shown in Scheme 9. ##STR8##
The single solvent strategy until this point, as shown in Schemes 6, 7, 8 and 9, and the capability of transferring a crude reaction mixture through the above-described steps without isolation of the intermediates resulted in up to 70% yield (based on cyclopentanecarboxylic acid) of tiletamine free base. The conversion of tiletamine to its hydrochloride salt in o-dichlorobenzene at this stage allows for the use of only a single solvent throughout the entire process. However, a reaction of hydrogen chloride gas with tiletamine in o-dichlorobenzene was found to result in conversion of only about 39% of the available free base to the hydrochloride salt. Therefore, a different solvent was used for the final reaction to obtain higher conversion. In the prior art method diethyl ether was the solvent of choice for this step, but diethyl ether is flammable and very difficult to handle. We have found that the use of n-butyl ether or t-butyl methyl ether and HCl gas result in the complete conversion of tiletamine to the corresponding hydrochloride salt, as shown in the acid addition salt reaction of Scheme 10. ##STR9##
As described above, synthesis of cyclopentyl 2-thienyl ketone, tiletamine and tiletamine acid addition salts has the following distinct advantages:
1. Tiletamine and its hydrochloride salt are produced with high yield. PA1 2. The multi-solvent process can be replaced by a procedure, employing only one solvent for the synthesis of tiletamine free base--two solvents for good yields of tiletamine acid addition salts, involving a second solvent only at the acid addition salt step of the process. PA1 3. A crude reaction mixture can be carried through six steps while avoiding complicated work ups, isolations, and purifications of the intermediates.